1. Field of the Invention
This invention concerns antiestrogenic compounds useful for their antineoplastic properties.
2. Discussion of the Background of the Invention
Approximately 55% of all human breast cancers are considered to be estrogen dependent. This means that these tissues contain cells that bind estrogens through an absorption and transport mechanism that allows the entry of estrogens into the cell. It is believed that estrogen receptors (which are proteins) originate in the cytoplasm of cells and initially interact with extracellular estrogens in the cell membranes to bind the estrogen to the protein receptor, as shown in FIG. 1. The protein receptor then folds on the estrogen to form a "cocoon-like" structure, thereby completing the tertiary structure of the receptor complex which stimulates the translocation of the receptor-estrogen complex through the pores of the nuclear membrane. The receptor protein must undergo an allosteric change in its conformation before the complex has the ability to bind to DNA. A hypothetical structure for such a tertiary estrogen-protein receptor complex which has undergone an allosteric change and assumed the "cocoon-like" structure is shown in FIG. 2.
The receptor protein must undergo this allosteric change in its conformation before the complex has the ability to bind to DNA. Once inside the nucleus, the activated receptor initiates transcription of genetic information from the DNA thereby forming m-RNA which is in turn a template for the linking of amino acids into proteins needed for cell membrane replication.
The antiestrogen effects produced by drugs such as tamoxifen (Nolvadex.RTM.) appear to be one of preventing the estrogen receptor from interacting with DNA in the nucleus to stimulate RNA and protein synthesis. This action initiates a block in the synthesis of macromolecules such as proteins, causing cell damage and ultimate death of the cell.
Antiestrogens are believed to be lipophilic molecules having a portion of the molecule which resembles naturally occurring estrogens. This portion of the antiestrogen selectively binds to the estrogen receptors. The antiestrogens, however, have a side chain arm (e.g. dimethylaminophenyl ethoxy) which distorts the three-dimensional configuration of the estrogen receptor preventing translocation of the receptor to the nucleus (see FIG. 3). A tertiary complex between chemical and receptor cannot form, thus cytoplasmic proteins which are usually synthesized in response to the translocation of the estrogen receptor are accordingly not produced, the cells are not able to replicate, and they die. Therefore, any agent that interferes with the final complex of drug and receptor ties up the receptor and prevents estrogen from entering the cells and/or blocks the DNA-RNA-protein cascade.
FIG. 3 shows an estrogen receptor occupied by tamoxifen wherein the dimethyl amino side chain arm prevents the receptor from forming the "cocoon-like" structure that was shown in FIG. 2. Prevention of this allosteric tertiary change prevents translocation of the occupied receptor to the nucleus.
Antiestrogens are useful in impairing growth and/or destroying estrogen dependent tumor cells because such cells require estrogen hormones for growth.
Tamoxifen (Nolvadex.RTM.) is a non-steroidal estrogen antagonist which is currently used in the treatment of breast cancer. The tamoxifen molecule binds to the receptor, but tamoxifen contains a dimethyl-aminophenyl ethoxy arm which apparently distorts the three-dimensional shape of the receptor molecule and inhibits the translocation of estrogenic information to the nucleus. Unfortunately, tamoxifen undergoes an isomerization under physiological conditions from the therapeutically useful trans configuration (antiestrogenic) to a cis form of the drug (estrogenic). This is a serious drawback since the antiestrogenic compound, after isomerization to an estrogenic compound, begins satisfying the estrogenic requirements of the tumor cell. In addition, the presence of an estrogen-like substance in the body results in stimulation of hypertrophy of the uterine endometrium with intermittent vaginal bleeding, especially in elderly females in whom the agent is most effective. In addition, tamoxifen is not an effective anti-cancer agent in the presence of physiological amounts of estradiol in an estrogen dependent human breast cancer cell line (ZR-75-1).
Most of the other available antiestrogens also have geometric centers about which trans/cis isomerization occurs. They accordingly undergo isomerization and have both estrogenic and anti-estrogenic properties. Other experimental antiestrogenic agents have the additional drawback of containing an ethyl pyrrolidine group (Lilly's Ly 156758 and Upjohns' Nafoxadine) which causes allergic reactions, such as corneal ulceration, in sensitive human individuals.
It is an object of the present invention to provide antiestrogenic compounds which do not undergo isomerization to an estrogenic compound under physiological conditions.
It is another object of the present invention to provide compounds with minimum estrogenic activity which thereby reduces endometrial stimulation and hypertrophy of the uterus.
It is also an object of the invention to provide an antiestrogen having minimal allergic side effects.